TIM-3⁺ CD8 T cells with a terminally exhausted phenotype retain functional capacity in hematological malignancies

Chronic antigen stimulation can drive CD8 T cell exhaustion and dysfunction among multiple T cell subsets. Using a murine myeloma model, Minnie et al. characterized a terminally exhausted CD8 T cell subset in the bone marrow tumor microenvironment that expressed not only transcription and epigenetic factors associated with exhaustion but also effector molecules, including IFN-gamma, granzymes, and perforin. This subset, IFN-gamma(+) TPHEX (IFN-gamma-secreting, phenotypically exhausted T cells), could kill myeloma cells, and IFN-gamma(+) TPHEX differentiated from CD19-targeted chimeric antigen receptor T cells could kill CD19(+) tumor cells. An analogous IFN-gamma(+) TPHEX subset was also detected in patients with myeloma and lymphoma. Together, these findings suggest that IFN-gamma(+) TPHEX have dysfunctional features but retain functionality, facilitating antitumor responses. -Christiana Fogg